Olfactory dysfunction is common in Parkinson disease (PD) and has been attributed to early deposition of a-synuclein pathology in the olfactory bulb. The pathophysiology of hyposmia in PD, however, remains poorly understood. Neurodegeneration within more central or limbic cortical components of the olfactory system may contribute to PD hyposmia. Deficits of olfactory function in PD are described in odor identification, odor discrimination, threshold detection, and odor recognition memory. A preferential decline in odor identification rather than odor detection suggests impairment in odor memory, possibly due to hippocampal dysfunction. We reported previously that impaired odor identification in (very) early PD is more closely correlated with hippocampal than striatal dopaminergic denervation. These findings suggest that hippocampal dopaminergic denervation and/or dysfunction may contribute to PD hyposmia. Olfactory impairments, however, are not affected by dopaminergic medications, and do not correlate with PD disease stage or duration of motor features of PD. This suggests an early floor phenomenon in the effect of dopaminergic denervation on hyposmia. Hyposmia occurs also in Alzheimer disease (AD) and increases with severity of dementia. Higher density of entorhinal cortex and hippocampal neurofibrillary tangles correlates with greater odor identification deficits, suggesting a role for hippocampal formation dysfunction in AD hyposmia. Another contributor to AD hippocampal dysfunction is loss of basal forebrain cholinergic innervation, an early phenomenon in AD. Cholinergic system degeneration is an early feature of PD also, at least in a subset of patients, and worsens with the appearance of dementia. Most studies of olfaction and PD are cross-sectional in nature and do not include subjects with cognitive impairment. However, worsening hyposmia in advancing PD may be associated with cholinergic neuron degeneration and associated cognitive dysfunction. Our preliminary data indicates correlation between the severity of PD hyposmia and declining hippocampal cholinergic innervation. PD hyposmia is predicted, then, to be most marked in PD subjects with evidence of early cognitive dysfunction; a prediction borne out by our preliminary data. The goals of this prospective cohort study are to test 2 hypotheses. One, greater severity of hyposmia is associated with increased risk of cognitive decline in subjects with advancing PD. Two, worsening hyposmia parallels progressive cholinergic hippocampal denervation. If these hypotheses are confirmed, olfactory function evaluations may provide a unique biomarker for efficient clinical screening to identify PD subjects with a central cholinergic deficit at high risk for cognitive decline. PUBLIC HEALTH RELEVANCE: Non-motor features such as dementia, are major determinants of disability and reduced health- related quality of life in Parkinson disease. Olfactory testing, perhaps combined with other tests, could be used to identify Parkinson disease subjects at high risk for cognitive decline. Results of this project may provide the foundation for unique biomarker information to guide annual clinical smell test screening in clinical practice - a window to guide targeted intervention in subjects with a central cholinergic deficit at highest risk of dementia.